Genetic Variant AFF2:c.*7233A>G (chrX-148998565-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002025.4(AFF2):c.*7233A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 111,386 control chromosomes in the GnomAD database, including 682 homozygotes. There are 3,561 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.12 ( 682 hom., 3551 hem., cov: 23)

Exomes 𝑓: 0.052 ( 0 hom. 10 hem. )

Consequence

AFF2
NM_002025.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.592

Publications

7 publications found

Variant links:

Genes affected

AFF2 (HGNC:3776): (ALF transcription elongation factor 2) This gene encodes a putative transcriptional activator that is a member of the AF4\FMR2 gene family. This gene is associated with the folate-sensitive fragile X E locus on chromosome X. A repeat polymorphism in the fragile X E locus results in silencing of this gene causing Fragile X E syndrome. Fragile X E syndrome is a form of nonsyndromic X-linked cognitive disability. In addition, this gene contains 6-25 GCC repeats that are expanded to >200 repeats in the disease state. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Jul 2016]

AFF2 Gene-Disease associations (from GenCC):

FRAXE intellectual disability
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

AFF2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4 link	c.*7233A>G		3_prime_UTR_variant	Exon 21 of 21	ENST00000370460.7	NP_002016.2	P51816-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF2	ENST00000370460.7 link	c.*7233A>G		3_prime_UTR_variant	Exon 21 of 21	5	NM_002025.4	ENSP00000359489.2		P51816-1
AFF2	ENST00000286437.7 link	c.*7233A>G		3_prime_UTR_variant	Exon 18 of 18	2		ENSP00000286437.5		P51816-7

Frequencies

GnomAD3 genomes

AF:

0.118

AC:

13135

AN:

111023

Hom.:

681

Cov.:

show subpopulations

Gnomad AFR

AF:

0.190

Gnomad AMI

AF:

0.320

Gnomad AMR

AF:

0.0733

Gnomad ASJ

AF:

0.121

Gnomad EAS

AF:

0.0230

Gnomad SAS

AF:

0.0523

Gnomad FIN

AF:

0.0692

Gnomad MID

AF:

0.0681

Gnomad NFE

AF:

0.0992

Gnomad OTH

AF:

0.106

GnomAD4 exome

AF:

0.0525

AC:

AN:

305

Hom.:

Cov.:

AF XY:

0.0752

AC XY:

AN XY:

133

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.0537

AC:

AN:

298

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.118

AC:

13138

AN:

111081

Hom.:

682

Cov.:

AF XY:

0.107

AC XY:

3551

AN XY:

33305

show subpopulations

African (AFR)

AF:

0.190

AC:

5779

AN:

30433

American (AMR)

AF:

0.0729

AC:

764

AN:

10479

Ashkenazi Jewish (ASJ)

AF:

0.121

AC:

320

AN:

2643

East Asian (EAS)

AF:

0.0231

AC:

AN:

3551

South Asian (SAS)

AF:

0.0517

AC:

135

AN:

2612

European-Finnish (FIN)

AF:

0.0692

AC:

415

AN:

6001

Middle Eastern (MID)

AF:

0.0698

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0991

AC:

5249

AN:

52949

Other (OTH)

AF:

0.107

AC:

163

AN:

1522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

423

846

1268

1691

2114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

146

292

438

584

730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.108

Hom.:

10332

Bravo

AF:

0.127

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

6.4

(source)

DANN

Benign

0.79

PhyloP100

-0.59

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over